Migraine is a debilitating neurological condition involving the neuropeptide calcitonin gene-related peptide (CGRP). The overall objective of this project is to identify mechanisms by which CGRP triggers photophobia, a common symptom of migraine. Photophobia is a painful response to ordinarily non-painful levels of light. A useful tool for these studies is the nestin/hRAMP1 transgenic mouse, which is sensitized to CGRP actions. The mice have elevated nervous system expression of a subunit of the CGRP receptor called human receptor activity-modifying protein 1 (hRAMP1). Nestin/hRAMP1 mice have heightened responses to at least two sensory stimuli: touch and light. The light aversive phenotype is analogous to photophobia and is greatly enhanced by central administration of CGRP. The mice also display enhanced light aversive behavior following chemically induced mast cell degranulation and a mild stress paradigm. Stress is one of the most common triggers of migraine and also induces dural mast cell degranulation. There is evidence that migraine is a neural disorder that can be exacerbated by inflammatory signals: dural mast cells activate trigeminal nociceptive pathways, mast cell degranulation triggers migraine-like headaches, and anti-inflammatory drugs are commonly used for migraine. We hypothesize that CGRP can act in the thalamus to trigger light aversion following stress-induced neurogenic inflammation. This hypothesis is based on a recent finding that posterior thalamic neurons are sensitive to both dural and light stimulation. Furthermore, CGRP can activate dural mast cells, trigeminal neurons, and posterior thalamic neurons. Thus, there is a CGRP-dependent pathway for stress-induced mast cell activation to sensitize thalamic neurons to light, leading to photophobia. The first aim will establish the contribution of mast cells in light aversive behavior. Light aversion in response to a chemical activator and a mild stress paradigm will be compared between nestin/hRAMP1 and control mice. The second aim will identify whether the posterior thalamus is a CNS target of CGRP- and mast cell-induced light aversion. Complementary pharmacological and genetic strategies will be used. These aims will provide insight to the mechanisms by which stress can trigger a migraine-like symptom in an animal model. Clearly, a host of genes will be involved in migraine in addition to CGRP. Hence, the hRAMP1-based strategy provides an innovative approach using the advantages of a defined mouse system for the study of complex diseases. The significance of the proposed studies is their translational potential, which is underscored by the prevalence of migraine, affecting almost 1 in every 5 women. Despite advances in our understanding of migraine over the past decade, many questions remain unanswered, in part due to the paucity of appropriate animal models. To address these issues, we have assembled an interdisciplinary team with expertise in CGRP, migraine, pain pharmacology, and mouse behavior. The impact of this proposal will be a validated preclinical model for translational studies to develop new therapeutics for migraine.